Is MACF1 p.Pro3389Ser (c.10165C>T) pathogenic?

MACF1 p.Pro3389Ser (c.10165C>T) is classified Uncertain significance in MACF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.1264); Very rare (popmax 0.00223%, eas); Associated with lissencephaly 9 with complex brainstem malformation.

What condition is associated with MACF1 p.Pro3389Ser (c.10165C>T)?

MACF1 p.Pro3389Ser (c.10165C>T) is associated with lissencephaly 9 with complex brainstem malformation (ClinVar).

How common is MACF1 p.Pro3389Ser (c.10165C>T) in the general population?

MACF1 p.Pro3389Ser (c.10165C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MACF1 p.Pro3389Ser (c.10165C>T)?

AlphaMissense predicts likely benign (score 0.1264) — an in-silico prediction, not a clinical call.

MACF1 p.Pro3389Ser

c.10165C>T · VCV4531462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1264 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

lissencephaly 9 with complex brainstem malformation

Computational evidence

Protein change
AlphaMissense	0.1264	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.03, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 14 kb · p 0.96 · regional, not allelic
Overall
CADD	16.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P3394S vs ClinVar P3389S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Overall 0.000124% 2/1,613,982 alleles · very rare exomes 1/1,461,798 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
East Asiangrpmax	0.00223%	44,886

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MACF1
Protein: p.Pro3389Ser
Coding: c.10165C>T
MANE Select: NM_001394062
Type: single nucleotide variant
Location: chr1:39337281 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)

Full MACF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lissencephaly 9 with complex brainstem malformation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MACF1 p.Arg7251Pro Likely pathogenic ★★ same condition
MACF1 p.Arg30Gln Uncertain significance ★★ same condition
MACF1 p.Arg3713Cys Uncertain significance ★★ ⚠ same condition
MACF1 p.Arg6864Gln Uncertain significance ★★ same condition
MACF1 p.Arg7005Trp Uncertain significance ★★ ⚠ same condition
MACF1 p.Glu6915Lys Uncertain significance ★★ same condition
MACF1 p.Ile380Thr Uncertain significance ★★ ⚠ same condition
MACF1 p.Leu6865Phe Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/macf1-p-pro3389ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown